1. Technical Field
The subject invention relates to methods of using 27-hydroxycholesterol, sterol-27-hydroxylase, and related compounds in the prevention of restenosis. The subject invention also relates to methods of using 27-hydroxycholesterol in the treatment of cancer.
2. Background Information
Various surgical bypass and angiographic procedures are routinely employed for increasing blood flow to an organ, usually the heart. These operative and non-operative procedures injure, to a greater or lesser extent, the interior wall of the lumen of the blood vessel at the target site. This endothelial injury often leads through a cascade of events to restenosis. For example, balloon, laser or rotameter angioplasty, in which a catheter is inserted into the arterial system to place a balloon, laser or blade at the stenosis, is quite successful in widening a narrowed area of a blood vessel lumen. However, endothelial injury occurs at the site of the lesion, leading to restenosis in an estimated 20-40% of patients.
It has been shown in animals that endothelial injury initiates a process that leads to narrowing of the injured artery (stenosis), and this model is related and is used to study the events that occur following endothelial injury.
The major current theory for explaining restenosis is that once the endothelial cells are injured or removed by the invasive procedure, circulating platelets cover the denuded areas and release potent growth factors, such as platelet derived growth factor, which stimulate the growth and migration of underlying smooth muscle cells. Other growth factors, such as fibroblast growth factors, have also been implicated. For these reasons, anti-growth factors are being evaluated for the prevention of atherosclerosis.
Many factors are thought to potentially participate in restenosis. Further, hemodynamic forces responsible for the original lesion are not generally alleviated by angioplasty and may be aggravated at plaque disruption. The thrombo-resistant nature of the arterial lumen is reduced due to the generation of markedly thrombogenic surfaces of complex geometrical configuration, and changed permeability characteristics permitting possible direct interaction between blood-borne elements such as the aforementioned platelets and the arterial lumen. In summary, the surgical and angiographic procedures necessarily result in injury to vessel walls, which results in restenosis in 20-40% of patients.
27-hydroxycholesterol (cholest-5-ene-3.beta.,27-diol) is normally present in biological fluid after neonatal life. Recently, the IUB changed certain rules of nomenclature, and the compound now referred to as 27-hydroxycholesterol was previously called 26-hydroxy-cholesterol. Two methyl groups are attached to carbon number 25 of cholesterol, but only one can be enzymatically hydroxylated, which was previously named carbon number 26, but is now named as carbon number 27.
U.S. Pat. No. 4,427,688 by Javitt describes the administration of 26-hydroxycholesterol (sic., 27-hydroxycholesterol) and various derivatives and analogs thereof for reducing cholesterol synthesis and/or cholesterol accumulation in the body tissues; hence, teaching the use of 27-hydroxycholesterol compounds for the treatment of atherosclerosis. Thereafter, as disclosed in U.S. Pat. No. 4,939,134, Javitt, et al. discovered that 27-aminocholesterol, and certain amino-substituted analogs and derivatives thereof, are more potent inhibitors of cholesterol synthesis and accumulation than 27-hydroxycholesterol.
Javitt filed Japanese Application 107488/82 in 1982, published as 019206/91 on Nov. 14, 1991 ("JPA"), largely corresponding in disclosure to U.S. Pat. No. 4,427,688 with insertion of additional information for further supporting use of 27-hydroxycholesterol in treatment of atherosclerosis. The JPA notes that Kandutsch, et al., Science, 201, 498 (1978) mentioned that oxygenated cholesterol has an inhibitory effect on the proliferation of fibroblasts and lymphocytes in vitro, perhaps by inhibiting HMG CO-A reductase, the rate-limiting enzyme in cholesterol biosynthesis, which is consistent with the idea that cholesterol is essential to cell proliferation. Javitt tested this theory by seeding hamster aortic smooth muscle cells at low density in culture wells and coulter counting control and 27-hydroxycholesterol exposed cells six days later. The 27-hydroxycholesterol at the tested concentration inhibited the proliferation by about 50%. Although a potential lead, in vitro muscle cell proliferation inhibition, in itself, does not teach nor suggest the use of the same substance for preventing restenosis in vivo. Indeed, some have interpreted the inhibitory effect by oxysterols on vascular smooth muscle cells as a toxic effect. Zhou, et al., Proc. Soc. Exp. Biol. Med., 202:75-80; Nassem, et al., Biochem. Internat., 14:71-84. Also see Baranowski, et al., Atherosclerosis, 41:255-260. Further, it has been recently reported that high doses of Lovastatin, a potent cholesterol lowering drug, in a randomized, double blind placebo controlled trial, did not decrease restenosis six months following percutaneous transluminal coronary angioplasty, although the Lovastatin did markedly decrease LDL-cholesterol level, as expected. Thus, as of today, the cholesterol lowering biological activity of a drug, while perhaps indicating potential use in the treatment of atherosclerosis, is not predicative nor suggestive of use for combating restenosis. As discussed above, restenosis is a multi-faceted phenomena, distinct from atherosclerosis, and the mechanism of which is, at best, only partially understood.
All U.S. patents and publications referred to herein are hereby incorporated by reference.